Virus-targeted therapeutic for EBV-Associated Malignancies

EBV 相关恶性肿瘤的病毒靶向治疗

• 批准号: 9312763
• 负责人: SUSAN Park PERRINE
• 金额: $ 51.96万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312763
• 关键词: Acquired Immunodeficiency Syndrome; Adverse event; African Burkitt' s lymphoma; Animal Model; Antiviral Agents; B-Cell Lymphomas; Breast Carcinoma; Burkitt Lymphoma; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Data; Databases; Development; Drug Exposure; EBV-associated malignancy; Enzymes; Family; Ganciclovir; Gene Expression; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Lead; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Measurable; Nasopharynx Carcinoma; Neoplasms; Normal Cell; Oral; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Play; Population; Prodrugs; Protein Kinase; Protocols documentation; Radiation; Radiation therapy; Refractory; Regimen; Research Personnel; Resistance; Role; Safety; Site; Small Business Innovation Research Grant; Stomach Carcinoma; System; TK Gene; Therapeutic; Thymidine Kinase; Toxicology; Transplantation; Treatment Protocols; Validation; Viral; Viral Drug Resistance; Viral Genome; Virus; antiviral nucleoside analog; chemotherapy; design; gammaherpesvirus; killings; meetings; member; neoplastic cell; nucleoside analog; oncology; outcome forecast; partial response; pre-clinical; preclinical development; prototype; public health relevance; research clinical testing; response; sarcoma; targeted treatment; therapeutic evaluation; tumor; virus development

 DESCRIPTION (provided by applicant) Epstein-Barr virus (EBV) is associated with a number of human malignancies, and likely plays a causal role in two endemic tumors: African Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). Clonal EBV can be found in Burkitt's lymphomas, T/NK lymphomas, and post-transplant lymphoproliferative disorders (LPD), as well as some T- and B-cell lymphomas, and half of Hodgkin's lymphomas. In addition, EBV may be involved in the development of other neoplasias, including AIDS-related sarcomas, and gastric carcinomas, and certain breast carcinomas. However, we have demonstrated that merely the very presence of the virus in a tumor provides the opportunity for a targeted therapeutic strategy. EBV persists in these tumors in a dormant or "latent" state. Many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral pro-drugs like ganciclovir, which targe the viral thymidine kinase (TK) enzyme. EBV is resistant to these antiviral agents because latently-infected tumor cells do not express the viral (TK) enzyme. We have demonstrated that selected agents which induce the EBV-TK gene expression in the tumor cells renders the tumor susceptible to standard anti-viral agents. This is a tumor-targeted therapy, in that only the tumor cells (containing EBV) are killed - normal cells are spared. We have conducted a successful Phase I/II study of this virus-targeted therapeutic approach in patients with EBV-associated lymphoid malignancies, all of which were resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 26% of patients, and good partial responses (PRs) in an additional 40% within one treatment cycle (total tumor response rate of 67%). This is an exceptionally high rate of response, and the adverse event profile was favorable. The overall goal of this SBIR proposal is to develop a more potent, more selective, and more patient-accessible virus-targeted therapeutic for testing in EBV+ malignancies. In our Phase I period, we have screened, validated, and selected a highly-potent, clinical-stage lead inducing agent, which is orally-available and has significant human safety data, for use in combination with an anti-viral agent for EBV lymphomas. In this Phase II proposal, we will complete the preclinical development of the virus-inducing agent for this specific indication, generate data to expand its potential therapeutic application and value, and prepare for a Phase II proof-of-concept clinical trial. Our Specific Aims in this Phase II Proposal are: 1.) Optimize lead compound - Refine this EBV/KSHV-targeted therapeutic regimen in animal models; 2.) Expand application of this therapeutic approach into other herpesvirus-associated malignancies; 3.) Complete pre-clinical development; 4.) Clinical trial planning and set-up. Measurable Outcomes and Deliverables: i.) Optimization of treatment regimen; ii.) Validation of this virus-targeted approach in other malignancies associated with γ-herpesviruses; iii.) Complete pre-clinical development of lead compound; iv.) Filing of IND for phase II clinical trial.

 描述（由申请人提供） EB 病毒（EBV）与多种人类恶性肿瘤相关，并且可能在两种地方性肿瘤中起因果作用：非洲伯基特淋巴瘤（BL）和鼻咽癌（NPC）。克隆性 EBV 可见于伯基特淋巴瘤、T/NK 淋巴瘤和移植后淋巴增殖性疾病 (LPD)，以及一些 T 细胞和 B 细胞淋巴瘤以及一半的霍奇金淋巴瘤。此外，EBV可能参与其他肿瘤的发生，包括艾滋病相关肉瘤、胃癌和某些乳腺癌。然而，我们已经证明，仅仅病毒在肿瘤中的存在就为靶向治疗策略提供了机会。 EBV 在这些肿瘤中以休眠或“潜伏”状态持续存在。许多疱疹家族病毒感染的细胞可以被核苷类似物抗病毒前药（例如更昔洛韦）杀死，这些药物针对的是病毒胸苷激酶（TK）酶。 EBV 对这些抗病毒药物具有耐药性，因为潜伏感染的肿瘤细胞不表达病毒 (TK) 酶。我们已经证明，在肿瘤细胞中诱导 EBV-TK 基因表达的选定药物使肿瘤对标准抗病毒药物敏感。这是一种肿瘤靶向治疗，仅针对肿瘤 细胞（含有 EBV）被杀死 - 正常细胞幸免。我们已经在 EBV 相关淋巴恶性肿瘤患者中成功开展了这种病毒靶向治疗方法的 I/II 期研究，所有这些患者都对常规放疗和化疗具有耐药性。我们的靶向治疗在一个治疗周期内对 26% 的患者产生了完全临床缓解 (CR)，并在另外 40% 的患者中产生了良好的部分缓解 (PR)（肿瘤总缓解率为 67%）。这是一个非常高的反应率，并且不良事件的情况是有利的。该 SBIR 提案的总体目标是开发一种更有效、更具选择性、更易于患者使用的病毒靶向疗法，用于 EBV+ 恶性肿瘤的检测。在第一阶段阶段，我们筛选、验证并选择了一种高效、临床阶段的先导诱导剂，该药物可口服，并具有重要的人类安全性数据，可与 EBV 淋巴瘤的抗病毒药物联合使用。在这个二期提案中，我们将完成针对该特定适应症的病毒诱导剂的临床前开发，生成数据以扩大其潜在的治疗应用和价值，并为二期概念验证临床试验做好准备。我们在此 II 期提案中的具体目标是： 1.) 优化先导化合物 - 在动物模型中完善这种 EBV/KSHV 靶向治疗方案； 2.) 将这种治疗方法扩展到其他疱疹病毒相关恶性肿瘤； 3.) 完成临床前开发； 4.) 临床试验计划和设置。可衡量的结果和可交付成果：i.) 治疗方案的优化； ii.) 在与 γ-疱疹病毒相关的其他恶性肿瘤中验证这种病毒靶向方法； iii.) 完成先导化合物的临床前开发； iv.) 提交II期临床试验IND。